Process for preparing iodinateix



Patented Jan. 3, 1950 PROCESS FOR PREPARING IODINATED Z-AMINO-THIAZOLE Yvonne Garreau-,. Paris, France, assignor to S- clcte Generale dApplicat-ions, Therapeutiques Theraplixfl'Paris, France No Drawing. Application May .6. 1947.-, SerialNo. 746 326. In France Marcl 1,25,l94 4 Section 1, Public Law 690-, August 8, 1946 Patent expires March 25, 1964 1 2 Claims. (61.260-302') The invention has for its object to provide a process for preparing 2-amino-thiazoles in which one of the carbon atoms which are not. linked tothe aminogroup is attached to an iodine atom.

There exist two isomeric varieties of these compounds which varieties are represented by the formulae:

in which R and R represent either hydrogen, or alkyl, alkylene, aryl, carboxyl, or acidyl groups (such as acetyl), whichmay be identical or different.

These substances are narcotics and can be used either as general anaesthetics which may be administered by injections in aqueoussolutions; in cachets or in pills, or as soporifics: in drops, cachets or pills.

They may be used as starting'materials for the synthesis of iodinated sulfamides. be used for administering iodine.

The applicant has discovered that it is possible to prepare these substances by the action of iodine chloride (ICl) on the bases or their salts, dissolved in an acid medium where the starting material is readily soluble, such as hydrochloric or acetic acid.

The reaction takes place in accordance with the following diagram:

Two cases may arise:

(c) There is no substitution at 4 or 5 (R represents hydrogen). In this case, iodination is effected on one or other of the two positions 4 or 5 and a complex mixture is precipitated.

(b) In the case in which the thiazole is substituted at 4 or at 5 (R represents an alkyl, aryl, carboxyl or other radical), the position 5 or 4. alone remaining available, iodination is efiected on the free position.

This process enables the iodinated compounds of the acetylated derivatives (R') of the amine function of the Z-amino-thiazoles to be obtained.

They can also These compounds can be; obtained. either by directly iodinating the acetylated. derivatives, or on the contrary by acetylating the derivatives which have already been iodinated. In. both cas.es,. the acetylation. can be elfected, bymeans of acetic anhydride or of acetyl chloride- On the other hand,.all these iodinatedder-ivatives can form with iodine, chloride. (ICl) combinations of addition which are precipitated, in crystalline form when an excess of iodine chloride is. poured, into. a hydrochloride solution of the iodinated thiazole.

Example I.Case in which R is the. radical CH3 and R hydrogen (z-amino-d methyl-fiiodo-thiazole) 17 gm. of 2-amino-l-methyl-thiazole hydrochloride are dissolved in 560 cc. of water, to which 84 cc. of'hydrochloric acid have been added (11:1 .19). After cooling to a temperature below- 10 6.,12- gm. of iodine chloride are added. Pearly needles of 2.-amino-4-methyl-5- iodo-thiazolev hydrochloride quickly separate out andare drained. Yield: 15, gm. This product (melting .poi'nt.=160 C.) is very soluble in boiling water, boiling methyl and ethyl alcohols, insoluble in benzene, ether, acetone. From its hot aqueous solution to which ammonia has been added, the base separates out in the form of scales (melting point=114 C.).

Example II.-Case in which R and R are hydrogen [2-amino-(4 or 5)-iodo-thiazole].

The technique is the same as hereinbefore, the 17 gm. of 2-amino-4-methyl-thiazo1e hydrochloride being replaced by an equivalent quantity of 2-amino-thiazole hydrobromide.

After concentrating, needles of 2-amino-(4 or 5) iodo thiazole hydrobromide (melting point=136) are obtained, which are fairly soluble in cold water. From the aqueous solution to which ammonia has been added, the base precipitates out in the form of scales (melting point=112 0.):

Example [IL-Case in which R. is the carboXyl radical COOH-, R hydrogen (2-aminothiazole-4 ;5-iodo-carboxylic acid) The technique is the same as hereinbefore, replacing the 17 gm. of 2-amino-4-methyl-thiazole hydrochloride by an equivalent quantity of 2- amino-4-thiazo1e-carboxylic acid.

Needles are obtained (melting point=220 C. decomposition) which are very soluble in boiling water, soluble in hot methyl and ethyl elcohols and soluble in dilute alkaline lyes.

Example I V.In the case in which R is hydrogen and R the acetyl radical CHa-CO-(2- acetylamino- (4 or 5) iodo-thiazole) 45 gm. of Z-acetyIamino-thiazole are dissolved in 100 cc. of crystallizable acetic acid and 45 gm. of iodine chloride are added. After several hours, the 2-acetylamino-(4 or 5) -iodo-thiazole is dried.

Needles are obtained (melting point=230 C. decomposition) which are insoluble in boiling water, soluble in boiling methyl and ethyl alcohols, less soluble in the cold state, soluble in hot acetone, insoluble in ether.

Emample V.-Case in which R is the methyl radical CH3 and R is the acetyl radical CH3CO (2-acetylamino-4-methyl-5-iodo-thiazole) The starting material comprising Z-acetylaminol-methyl-thiazole is treated according to the foregoing technique and produces needles (melting point=220 C.) which are very slightly soluble in boiling water, soluble in ethyl and methyl alcohols, insoluble in ether and benzene.

Example VI.-Case in which R. is the carboxyl radical COOH and R the acetyl radical CIIaCO- (Z-acetyIamino-thiazole 4;5 iodo carboxlylic acid).

The technique of Example I applied to the 2- acetylamino-4-thiazole-carboxylic acid produces scales (melting point above 310 C.) which are insoluble in boiling water, slightly soluble in boiling methyl and ethyl alcohols, soluble in dilute acetic acid and alkalis.

, soluble in water, methyl or ethyl alcohols.

As hereinbefore stated, it is possible, by means of the foregoing processes, to prepare compounds of addition with iodine chloride.

Emmple VII .Preparation of the combination of addition of iodine chloride and 2-acetylamino- 4-methyl-5-iodo-thiazole (compare with Example The combination of addition is immediately pre- 4 cipitated in the form of yellow needles (melting point=148 C.) This product loses 101 when heated or when dissolved in a solvent other than concentrated hydrochloric acid. Yield 38 gm.

Eazample VIII.--Preparation of the combination of addition of iodine chloride with the product of Example III (Z-amino-thiazole-;5-iodocarboxylic acid).

By applying a similar technique to that of Example VII, yellow scales are obtained (melting point=217-218 C. decomposition), which are in- By prolonged heating in water, this substance loses its iodine chloride.

As hereinbefore stated, the above described novel chemical compounds form narcotics. When used as anaesthetics, they should be given in a dose of about mgm. per kg. of body weight, in an aqueous solution nearly at saturation point, i. e. 2 to 5 gm. per cc. of water, or in cachets, or in pills with a usual excipient. When used as soporifics, they should be given in a dose of about 5 to 10 mgm. per kg. of body weight, in a concentrated solution or in cachets or pills.

Having now described my invention what I claim as new and desire to secure by Letters Patent is:

1. A process for preparing new iodine derivatives of 2-amino-thiazole which comprises reacting iodine chloride with a Z-amino-thiazole in the presence of an acid wherein the 2-aminothiazole is readily soluble.

2. A process as claimed in claim 1 for preparing compounds of addition of the said iodine derivative with iodine chloride, which comprises precipitating said derivative in a hydrochloric medium with iodine chloride.

YVONNE GARREAU.

REFERENCES CITED The following references are of record in the file of this patent:

Ochiai et al.: Berichte 72B-1939, pp. 1470-1476. Chemical Abstracts, vol. 40, page 2445 (citing Comptes Rendus, 218, pp. 597-598). 

1. A PROCESS FOR PREPARING NEW IODINE DERIVATIVES OF 2-AMINO-THIAZOLE WHICH COMPRISES REACTING IODINE CHLORIDE WITH A 2-AMINO-THIAZOLE IN THE PRESENCE OF AN ACID WHEREIN THE 2-AMINOTHIAZOLE IS READILY SOLUBLE. 